Helix mimetics and composition and methods related thereto

ABSTRACT

Compounds which mimic the secondary structure of helical regions of biologically active peptides and proteins having the following structure: 
                 
 
including pharmaceutically acceptable salts and stereoisomers thereof, wherein Y, A, B, R 1  and R 2  are as defined herein. Such compounds have utility over a wide range of applications, including use as diagnostic and therapeutic agents. In particular, compounds of this invention, and pharmaceutical compositions containing the same, are neurokinin (tachykinin) antagonists. Libaries contaning the compounds of this invention are also disclosed, as well as methods for screening such libaries identify biologically active members.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional PatentApplication No. 60/316,352, filed Aug. 29, 2001, where this provisionalapplication is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to helix mimetics, as well as tocompositions and methods related thereto, including chemical librariesof helix mimetics.

2. Description of the Related Art

Proteins are polymers of amino acids in which the carbon atoms and amidegroups alternate to form a linear polypeptide, with the amino acid sidechains projecting from the α-carbon atom of each amino acid. Thesequence of amino acids and location of disulfide bridges (if any) areconsidered the “primary” protein structure. The “secondary” structure ofa protein refers to the steric relationship of amino acid residues thatare in close proximity to one another in the linear sequence. Suchsteric relationships give rise to periodic structure, including thehelix. Helices comprise one of three classes of protein secondarystructure and display amino acid side chains in a fixed spatialrelationship to each other.

The helix is a rod-like structure wherein the polypeptide chain formsthe inner part of the rod, and the side chains extend outward in ahelical array. The helix is stabilized by hydrogen bonds between the NHand CO groups of the polypeptide chain. The two most common helices,3₁₀- and alpha-helices, are found in nature. The latter being the mostabundant secondary structure in proteins. More specifically, for3₁₀-helix, the hydrogen of the NH group of each amino acid (i.e., aminoacid residue “n”) is hydrogen bonded to the oxygen of the CO group thatis located three amino acid residues behind in the linear polypeptide(i.e., amino acid residue “n-3”). Such hydrogen bonding is illustratedbelow:

While only a single hydrogen bond is depicted above for purpose ofillustration, each of the CO and NH groups of the linear polypeptide arehydrogen bonded in the 3₁₀-helix. In particular, each amino acid isrelated to the next by a translation of 2.0 Å along the helix axis and arotation of 120°, which gives 3 amino acid residues per turn of the3₁₀-helix. The pitch of the 3₁₀-helix is 6.0 Å (the product of thetranslation, 2.0 Å, and the number of residues per turn, 3), and theradius of the 3₁₀-helix is 1.9 Å.

For alpha-helix, the most abundant secondary structure in proteins, thehydrogen of the NH group of each amino acid (i.e., amino acid residue“n”) is hydrogen bonded to the oxygen of the CO group that is locatedfour amino acid residues behind in the linear polypeptide (i.e., aminoacid residue “n-4”). Such hydrogen bonding is illustrated below:

Again, while only a single hydrogen bond is depicted above for purposeof illustration, each of the CO and NH groups of the linear polypeptideare hydrogen bonded in the alpha-helix. In particular, each amino acidis related to the next by a translation of 1.5 Å along the helix axisand a rotation of 100°, which gives 3.6 amino acid residues per turn ofthe alpha-helix. The pitch of the alpha-helix is 5.4 Å (the product ofthe translation, 1.5 Å, and the number of residues per turn, 3.6), andthe radius of the alpha-helix is 2.3 Å. The “screw sense” of thealpha-helix can be right-handed (clockwise) or left-handed(counter-clockwise). While a few left-handed alpha-helixes do exist,most alpha-helixes found in naturally occurring proteins areright-handed.

In the absence of interactions other than hydrogen-bonding, thealpha-helix is the preferred form of the polypeptide chain since, inthis structure, all amino acids are in identical orientation and eachforms the same hydrogen bonds. Thus, polyalanine (i.e.,{—NHCH(CH₃)CO—}_(r)) exists as an alpha-helix. However, the presence ofother amino acids within the polypeptide chain may cause instability tothe alpha-helix. In other words, the amino acid side chains do notparticipate in forming the alpha-helix, and may hinder or even preventalpha-helix formation. A striking example of such side chain dependencyon alpha-helix formation is polylysine (i.e.,{—NHCH((CH₂)₄NH₂)CO—}_(n)). At a pH below 10, the NH₂ moiety in the sidechain of lysine is charged (i.e., NH₃ ⁺), and electrostatic repulsiontotally destroys the alpha-helix structure. Conversely, at a pH above10, the alpha-helix structure is preferred.

The helix constitutes one of the principle architectural features ofpeptides and proteins, and are important structural elements in a numberof biological recognition events, including ligand-receptorinteractions, protein-DNA interactions, protein-RNA interactions, andprotein-membrane interactions. A number of alpha-helix mimetics havebeen developed to stabilize the alpha-helical structure of a natural orsynthetic peptide or protein, particularly the secondary structure ofhelices. For example, U.S. Pat. Nos. 5,446,128, and 5,710,245 disclosecompounds that initiate and stabilize the three-dimensional structure ofthe helix, while U.S. Pat. Nos. 5,840,833 and 5,859,184 disclosecompounds with covalent bonds linking the inner core or backbone of thehelix, and thus stabilize the three-dimensional structure of the helix.

In view of the important biological role played by the helix, there is aneed in the art for compounds that can mimic the helix structure. Thereis also a need in the art for methods of making stable helix mimetics,as well as the use of such stabilized structures to effect or modifybiological recognition events which involve helical structures. Thepresent invention fulfills these needs and provides further relatedadvantages.

SUMMARY OF THE INVENTION

In brief, the present invention is directed to conformationallyconstrained compounds which mimic the secondary structure of helicalregions of biologically active peptides and proteins (also referred toherein as “helix mimetics”). The compounds of the present invention maygenerally be characterized as “fused bicyclo compounds” and have thefollowing general structure (I):

including pharmaceutically acceptable salts and stereoisomers thereof,wherein A, B, Y, R₁ and R₂ are as defined below.

The present invention is also directed to libraries containing compoundsof structure (I), as well as methods for synthesizing such libraries andmethods for screening the same to identify biologically activecompounds. In addition, compositions containing a compound of thisinvention in combination with a pharmaceutically acceptable carrier aredisclosed. Methods for treatment and/or prevention of central nervoussystem disorders, as well as other disorders, with the compounds andcompositions of this invention are also disclosed.

These and other aspects of this invention will be apparent uponreference to the following detailed description. To this end, variousreferences are set forth herein which describe in more detail certainprocedures, compounds and/or compositions, and are incorporated byreference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is generally directed to helix mimetics, The helixmimetics of the present invention are useful as bioactive agents,including (but not limited to) use as diagnostic, prophylactic and/ortherapeutic agents for central nervous system disorders, as well asother disorders as discussed herein. Chemical libraries of helixmimetics, which are usefull in the identification of bioactive agents,are also disclosed. In the practice of the present invention, thelibraries may contain from tens to hundreds to thousands (or greater) ofindividual helix mimetics (also referred to herein as “members”).

In one aspect of the present invention, compounds are disclosed thatmimic the secondary structure of helical regions of biologically activepeptides and proteins (also referred to herein as “helix mimetics”).Such compounds may generally be referred to as having “fused bicyclocompounds” since two carbon atoms (separated by a nitrogen atom) serveas the bridging atoms for two fused rings. More particularly, the fusedbicyclo compounds of this invention have the following structure (I):

or a pharmaceutically acceptable salt or stereoisomer thereof,

wherein

-   -   Y is —N(R₃)C(═O)—, —N(R₃)—, —OC(═O—, —C—, —SO₂—, —SO— or —S—;    -   A is —(CR₄R_(4a))_(m)—;    -   B is —(CR₅R_(5a))_(n)—;    -   m is 1, 2, 3 or 4 when Y is —N(R₃)—, —O—, —SO₂—, —SO— or —S—;    -   m is 1, 2 or 3 when Y is —N(R₃)C(═O)— or —OC(═O)—;

n is 1, 2, or 3;

-   -   R₄ and R₅ are, at each occurrence, the same or different and        independently an amino acid side chain moiety or an amino acid        side chain derivative;

R_(4a) and R_(5a) are, at each occurrence, the same or different andindependently hydrogen, hydroxy, —COOH, —CONH₂, —R₆, —OR₆, —COOR₆, —COR₆or —CONHR₆;

R₆ is a lower alkyl optionally substituted with halogen or hydroxy;

R₂ is -Z-(amino acid side chain moiety) or -Z-(amino acid side chainderivative), where Z is a direct bond or —C(═O)—, —C(═O)O—, —C(═O)NH—,—C(═NH)—, —SO₂— or —P(O)_(2,3)—; and

R₁ and R₃ are the same or different and represent the remainder of themolecule;

wherein any two adjacent CH groups (i.e., CH—CH) or adjacent NH and CHgroups (i.e., NH—CH) of the fused bicyclo compound optionally form adouble bond (i.e., C═C or N═C, respectively);

and with the provisos that:

(a) when Y is —S— or —SO—, R₁ is not hydrogen; and

(b) when Y is —S— and m is 1, R4 and R_(4a) are not both methyl when R₁is —C(═O)W, where W is phenyl, benzyl, —CH₂0(phenyl) or —OC(═O)(benzyl).

As used herein, an “amino acid side chain moiety” refers to any aminoacid side chain moiety present in naturally occurring alpha-amino acidsand other “non-protein” amino acids. “Non-protein” amino acids refer toalpha-amino acids, beta-amino acids and gamma-amino acids which are notnaturally occurring, but which are commonly utilized by those in thefield of peptide chemistry when preparing synthetic analogues ofnaturally occurring peptides, including D and L forms. An “amino acidside chain moiety” as used herein, includes (but is not limited to) thenaturally occurring amino acid side chain moieties identified in Table 1below. Other naturally occurring amino acid side chain moieties of thisinvention include (but are not limited to) the side chain moieties of3,5-dibromotyrosine, 3,5-diiodotyrosine, hydroxylysine,γ-carboxyglutamate, phosphotyrosine, phosphothreonine and phosphoserine.In addition, glycosylated amino acid side chains may also be used in thepractice of this invention, including (but not limited to) glycosylatedthreonine, serine, glutamine and asparagine.

TABLE 1 Naturally Occurring Amino Acid Side Chain Moieties Side ChainMoiety Amino Acid —H Glycine —CH₃ Alanine —CH(CH₃)₂ Valine —CH₂CH(CH₃)₂Leucine —CH(CH₃)CH₂CH₃ Isoleucine —(CH₂)₄NH₂ Lysine —(CH₂)₃NHC(NH₂)NH₂Arginine

Histidine —CH₂COOH Aspartic acid —CH₂CH₂COOH Glutamic acid —CH₂CONH₂Asparagine —CH₂CH₂CONH₂ Glutamine

Phenylalanine

Tyrosine

Tryptophan —CH₂SH Cysteine —CH₂CH₂SCH₃ Methionine —CH₂OH Serine—CH(OH)CH₃ Threonine

Proline

Hydroxyproline

In addition, as used herein, an “amino acid side chain derivative”represents modifications and/or variations to amino acid side chainmoieties. For example, the amino acid side chain moieties of alanine,valine, leucine, isoleucine and phenylalanine may generally beclassified as alkyl, aryl or arylalkyl moieties, optionally substitutedwith one or more substituents as defined below. Accordingly,representative amino acid side chain derivatives include substituted orunsubstituted alkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl,heteroaryl and heteroarylalkyl moieties.

Examples of amino acid side chain derivatives include (but are notlimited to) hydroxylysine, homoserine, homotyrosine, homophenylalanine,citrulline, kynurenine, 4-aminophenylalanine, 3-(2-naphthyl)-alanine,3-(1-naphthyl) alanine, methionine sulfone, t-butyl-alanine,t-butylglycine, 4-hydroxyphenylglycine, aminoalanine, phenylglycine,vinylalanine, prop argyl-glycine, 1,2,4-triazolo-3-alanine,4,4,4-trifiuoro-threonine, thyronine, 6-hydroxytryptophan,5-hydro-xytryptophan, 3-hydroxykynurenine, 3-aminotyrosine,trifuoromethyl-alanine, 2-thienylalanine, (2-(4-pyridyl)ethyl)cysteine,3,4-dimethoxy-phenylalanine,3,5-bistrifluoro-phenylalanine,3-(2-thiazolyl)-alanine, ibotenic acid,1-amino-lcyclopentane-carboxylic acid, 1-amino-lcyclohexanecarboxylicacid, quisqualic acid, 3-trifiuoromethylphenylalanine,4-trifiuoromethylphenylalanine, cyclohexylalanine, cyclohexylglycine,thiohistidine, 3-methoxytyrosine, elastatinal, norleucinc, norvalinc,alloisoleucine, homoarginine, thioproline, dehydroproline,hydroxy-proline, isonipectotic acid, homoproline, cyclohexyl-glycine,α-amino-n-butyric acid, cyclohexylalanine, aminophenylbutyric acid,phenylalanines substituted at the ortho, meta, or para position of thephenyl moiety with one or two of the following: a (C₁-C₄) alkyl, a(C₁-C₄) alkoxy, halogen or nitro groups or substituted with amethylenedioxy group; β-2- and 3-thienylalanine, β-2- and3-furanylalanine, β-2-, 3- and 4-pyridylalanine, β-(benzothienyl-2- and3-yl)alanine, β-(1 and 2-naphthyl)alanine, O-alkylated derivatives ofserine, threonine or tyrosine, S-alkylated cysteine, S-alkylatedhomocysteine, O-sulfate, O-phosphate and O-carboxylate esters oftyrosine, 3-sulfo-tyrosine, 3-carboxy-tyrosine, 3-phospho-tyrosine,4-methane sulfonic acid ester of tyrosine, 4-methane phosphonic acidester of tyrosine, 3,5-diiodotyrosine, 3-nitro-tyrosine, ε-alkyl lysineand δ-alkyl ornithine, and the like. Any of these “amino acid side chainderivative” maybe substituted with a methyl group at the alpha, beta orgamma positions, a halogen at any aromatic residue on the amino sidechain, or an appropriate protective group at the O, N, or S atoms of theside chain moieties. Appropriate protective groups are disclosed in“Protective Groups In Organic Synthesis,” T. W. Greene and P. G. M.Wuts, J. Wiley & Sons, NY, MY, 1991.

To this end, the term “alkyl” is a straight chain or branched, cyclic ornoncyclic, saturated or unsaturated alkyl containing from 1 to 12 carbonatoms (also referred to herein as “C₁₋₁₂alkyl”). Similarly, a “loweralkyl” is as defined above, but contains from 1 to 4 carbon atoms (alsoreferred to herein as a “C₁₋₄alkyl”). Representative saturated straightchain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl,n-hexyl, and the like; while saturated branched alkyls includeisopropyl, sec-butyl, isobutyl, tert-butyl, isopcntyl, and the like.Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and the like. Unsaturated alkyls contain atleast one double or triple bond between adjacent carbon atoms (referredto as an “alkenyl” or “alkynyl,” respectively). Representative straightchain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl,2-butenyl, isobutenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl,2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like; whilerepresentative straight chain and branched alkynyls include acetylenyl,propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1butynyl, and the like. Representative unsaturated cyclic alkyls includecyclopentenyl and cyclohexenyl, and the like.

“Aryl” is an aromatic carbocyclic moiety contain from 6 to 12 carbonatoms (also referred to herein as a “C₁₋₁₂aryl”), such as phenyl andnaphthyl.

“Arylalkyl” is an alkyl having at least one alkyl hydrogen atom replacedwith an aryl moiety, such as benzyl, —(CH₂)₂phenyl, —(CH₂)₃phenyl,CH(phenyl)₂, and the like.

Similarly, the amino acid side chain moieties of histidine, tryptophan,proline and hydroxyproline may generally be classified as heterocyclieor heterocyclecalkyl moieties, optionally substituted with one or moresubstituents as defined below. Accordingly, representative amino acidside chain derivatives also include substituted or unsubstitutedheterocycle and heterocyclealkyl moieties.

As used herein, “heterocycle” means a 5- to 7-membered monocyclic, or 7-to 10-membered bicyclic, heterocyclic ring which is either saturated,unsaturated, or aromatic, and which contains from 1 to 4 heteroatomsindependently selected from nitrogen, oxygen and sulfur, and wherein thenitrogen and sulfur heteroatoms may be optionally oxidized, and thenitrogen heteroatom may be optionally quaternized, including bicyclicrings in which any of the above heterocycles are fused to a benzenering. The heterocycle may be attached via any heteroatom or carbon atom.Heterocycles include heteroaryls as defined below. Thus, in addition tothe heteroaryls listed below, heterocycles also include morpholinyl,pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactarmyl,oxiranyl, oxetanyl, aziridinyl, azetidinyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

“Heterocyclealkyl” means an alkyl having at least one alkyl hydrogenatom replaced with a heterocycle moiety, such as —CH₂(heterocycle),—(CH₂)₂(hetcrocycle), and the like.

“Heteroaryl” means an aromatic heterocycle ring of 5- to 10 members andhaving at least one heteroatom selected from nitrogen, oxygen andsulfur, and containing at least 1 carbon atom, including both mono- andbicyclic ring systems. Representative heteroaryls are pyridyl, furyl,benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl,indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl,benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl,quinazolinyl, and the like.

“Heteroarylalkyl” means an alkyl having at least one alkyl hydrogen atomreplaced with a heteroaryl moiety, such as —CH₂pyridinyl,—CH₂pyrimidinyl, and the like.

The term “substituted” as used herein means any of the above groups—thatis, alkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, heteroaryl orheteroarylalkyl—wherein at least one hydrogen atom is replaced with asubstituent. In the case of an oxo substituent (“═O”), two hydrogenatoms are replaced. A “substituent” in this regard is halogen, oxo,hydroxy, haloalkyl (such as trifluoromethyl), —R, —OR, —C(═O)R,—C(═O)OR, —C(═O)NRR, —NRR, —NRC(═O)R, —NRC(═O)OR, —NRC(═O)NRR, —OC(═O)R,—OC(═O)OR, —OC(═O)NRR, —SH, —SR, —SOR, —SO₂R, —NRSO₂R, —Si(R)₃, or—OP(OR)₃, wherein each occurrence of R is the same or different andindependently hydrogen, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, heterocycle, substitutedheterocycle, heterocyclealkyl or substituted heterocyclealkyl, orwherein any two R groups attached to the same nitrogen atom, takentogether with the nitrogen atom to which they are attached, form aheterocycle or a substituted heterocycle.

A “peptide” means at least two naturally occurring amino acids joinedvia a peptide bond. Depending upon the number of amino acids joined viapeptide bonds, the resulting peptide may also be referred to as a“polypeptide” or “protein.” Similarly, a “peptide derivative” means apeptide which has been covalently modified and/or which contains aminoacids other than alpha-amino acids. Representative peptide derivativesinclude peptides which are N-alkylated, N-acylated or N-sulfonylatcd atthe amino termini, with, for example, methyl, benzyl, acetyl, benzoyl,methanesulfonyl, phenylsulfonyl, allyloxycarbonyl, t-butyloxycarbonyl,benzyloxycarbonyl, or fluorenyloxycarbonyl moieties; peptides in whichthe carboxy termini are esterified (methyl, ethyl, benzyl) or reduced toa hydroxy or aldehyde; peptides which are N-alkylated at peptide bondswith, for example, methyl or 2-hydroxy-4-methoxybenzyl; and peptideswhich incorporate beta- or gamma-amino acids such as beta-alanine orgamma-aminobutyric acid.

A “linker” is any covalent bridging moiety that facilitates linkage of acompound of structure (I), through the respective R₁, R₂, R₃, R₄,R_(4a), R₅ and/or R_(5a) moiety, to another moiety, agent, compound,solid support, molecule, amino acid, peptide or protein. For example,the compounds of this invention may be linked to one or more knowncompounds, such as biotin, for use in diagnostic or screening assays.Furthermore, one (or more) of R₁, R₂, R₃, R₄, R_(4a), R₅ or R_(5a) maybe a linker joining the compound of structure (I) to a solid support(such as a support used in solid phase peptide synthesis). Examples ofsuch linkers include p-alkoxybenzyl alcohol, phenylacetamidomethyl, and2-chlorotrityl chloride. In one example, linkage to another moiety orcompound, or to a solid support, is at the R₁ or R₃ position.

A “solid support” means any composition of matter to which anothercompound is attached directly or attached through a linker and which isinsoluble in at least one solvent that the attached compound is solublein. Alternatively, a “solid support” may be a composition of matter withsimilar solubility characteristics to the attached compound, but whichmay be readily precipitated from solution and filtered off as a solid.Representative examples include polystyrene, polyethylene glycol,polystyrene grafted with polyethylene glycol, polyacrylamide,polyamide-polyethylene glycol copolymer, controlled-pore glass, andsilica.

The phrase “remainder of the molecule” means any moiety, agent,compound, solid support, molecule, linker, amino acid, peptide orprotein covalently attached to the helix mimetic at either the R₁ and/orR₃ positions, including amino acid side chain moieties, amino acid sidechain derivatives and peptide derivatives as defined above, as well asmoieties such as -Z-(amino acid side chain moiety) and -Z-(amino acidside chain derivative) where Z is as defined above in the context of theR₂ moiety. Accordingly, an alternative depiction of structure (I), thebond between the ring nitrogen atoms and the corresponding R₁ and R₃moieties may be left undefined, as represented by the followingstructure (I′) when Y is —N(R₃)— or —N(R₃)C(═O)—, and by the followingstructure (I″) when Y is —O—, —OC(═O)—, —SO₂—, —SO—, or —S—:

wherein “ - - - ” represents the remainder of the molecule joined to thecorresponding ring nitrogen through a covalent bond, and A, B, Y and R₂are as defined above.

With regard to stereoisomers, it should be understood that a solid linedesignation in Structure (I) for attachment of an R group to a chiralatom of the fused bicyclo rings indicates that these groups may lieeither below or above the plane of the page (i.e., “

R” or “

R”). All isorneric forms of the compounds of Structure (I) are includedwithin the present invention, including racemates, rauemic mixtures andindividual enantiomers or diasteromers. For example, the compounds ofthis invention have the stereoconformation of structure (la) whenintended to mimic a helix of L-form amino acids, and structure (Ib) whenintended to mimic a helix of D-form amino acids:

The term “pharmaceutically acceptable salt” is intended to encompass anyand all acceptable salt forms of the compounds of Structure (I). Forexample, the compounds of this invention may generally be utilized asthe free acid or free base, or used in the form of acid or base additionsalts, which addition salts are well known to those skilled in thepharmaceutical or formulation field.

In a first embodiment of structure (I), Y is —N(R₃) C(═O)— and thecompounds of this invention have the following structure (II):

including pharmaceutically acceptable salts and stereoisomers thereof,wherein A, B, R₁, R₂ and R₃ are as defined above.

In a more specific embodiment of structure (II), all occurrence of R₄,R_(4a), R₅ and R_(5a) are hydrogen, and the compounds of this inventionhave the following structure (II′):

including pharmaceutically acceptable salts and stereoisomers thereof,wherein m, n, R₁, R₂ and R₃ are as defined above.

In a more specific embodiment of structure (II′), m is 1, n is 1, andthe compounds of this invention have the following structure (II″):

including pharmaceutically acceptable salts and stereoisomers thereof,wherein R₁, R₂ and R₃ are as defined above.

In a more specific embodiment of structure (II″), R₁ and R₃ are the sameor different and independently an amino acid side chain moiety or aminoacid side chain derivative, R₂ is —C(═O)R₇, —C(═O)OR₇, —C(═O)NHR₇ or—SO₂R₇, where R₇ is an amino acid side chain moiety or an amino acidside chain derivative. In a still more specific embodiment, R₇ is aryl,arylalkyl, heterocycle, heterocyclealkyl or heteroarylalkyl optionallyand independently substituted with one or more halogen, —CF₃, —COOH,—NH2, —OH or —NO₂. In a still further embodiment, R₇ is alkyl orsubstituted alkyl. In a still further embodiment, R₇ is substitutedalkyl having the following structure —(CH₂)_(p)—NH₂ or—(CH₂)_(p)—N(R′)₂, where p is 2-6 and R′ is independently hydrogen,alkyl or heterocycle.

In a second embodiment of structure (I), Y is —N(R₃)— and the compoundsof this invention have the following structure (III):

including pharmaceutically acceptable salts and stereoisomers thereof,wherein A, B, R₁, R₂ and R₃ are as defined above.

In a more specific the embodiment of structure (III), all occurrence ofR₄, R_(4a),R₅ and R_(5a) are hydrogen, and the compounds of thisinvention have the following structure (III′):

including pharmaceutically acceptable salts and stereoisomers thereof,wherein m, n, R₁, R₂ and R₃ are as defined above.

In a more specific the embodiment of structure (III′), m is 2 and n is1, and the compound of this invention have the following structure(III″)

including pharmaceutically acceptable salts and stereoisomers thereof,wherein R₁, R₂ and R₃ are as defined above.

In a still more specific embodiment of structure (III″), includingpharmaceutically acceptable salts and stereoisomers thereof, R₁ is aminoacid side chain moiety or amino acid side chain derivative, R₂ and R₃are the same or different and independently —C(═O)—R₇, —C(═O)OR₇, —CNHR₇or —SO₂—R₇, where R₇ is an amino acid side chain moiety or an amino acidside chain derivative. In a still more specific embodiment of structure,R₇ is aryl, arylalkyl, heterocycle, heterocyclealkyl or heteroarylalkyloptionally and independently substituted with one or more halogen, —CF₃,—COOH, —NH₂, —OH or —NO₂. In a still further embodiment of structure, R₇is alkyl or substituted alkyl. In a still further embodiment, R₇ issubstituted alkyl having the following structure —(CH₂)_(p)—NH₂ or—(CH₂)_(p)—N(R′)₂, where p is 2-6 and R′ is independently hydrogen,alkyl or heterocycle.

In a third embodiment of structure (I), Y is —OC(═)O—, and the compoundsof this invention have the following structure (IV):

including pharmaceutically acceptable salts and stereoisomers thereof,wherein A, B, R₁, and R₂ are as defined above.

In a more specific embodiment of structure (IV), all occurrence of R₄,R_(4a), R₅ and R_(5a) are hydrogen, and the compounds of this inventionhave the following structure (IV′):

including pharmaceutically acceptable salts and stereoisomers thereof,wherein m, n, R₁ and R₂ are as defined above.

In still a more specific embodiment of structure (IV′), m is 1, n is 1and the compounds of this invention have the following structure (IV″):

including pharmaceutically acceptable salts and stereoisomers thereof,wherein R₁ and R₂ are as defined above.

In a fourth embodiment of structure (I), Y is —O—, the compounds of thisinvention have the following structure (V):

including pharmaceutically acceptable salts and stereoisomers thereof,wherein A, B, R₁, and R₂ are as defined above.

In a more specific embodiment of structure (V), all occurrence of R₄,R_(4a), R₅ and R_(5a) are hydrogen, and the compounds of this inventionhave the following structure (V′):

including pharmaceutically acceptable salts and stereoisomers thereof,wherein m, n, R₁, and R₂ are as defined above.

In a more specific embodiment of structure (V′), m is 1, n is 1 and thecompounds of this invention have the following structure (V″):

including pharmaceutically acceptable salts and stereoisomers thereof,wherein R₁ and R₂ are as defined above.

In a fifth embodiment of structure (I), Y is —SO₂—, the compounds ofthis invention have the following structure (VI):

including pharmaceutically acceptable salts and stereoisomers thereof,wherein A, B, R₁, and R₂ are as defined above.

In a more specific embodiment of structure (VI), all occurrences of R₄,R_(4a), R₅ and R_(5a) are hydrogen, and the compounds of this inventionhave the following structure (VI′):

including pharmaceutically acceptable salts and stereoisomers thereof,wherein m, n, R₁, and R₂ are as defined above.

In a more specific embodiment of structure (VI′), m is 1, n is 1 and thecompounds of this invention have the following structure (VI″):

including pharmaceutically acceptable salts and stereoisomers thereof,wherein R₁ and R₂ are as defined above.

In a sixth embodiment of structure (I), Y is —SO—, the compounds of thisinvention have the following structure (VII):

including pharmaceutically acceptable salts and stereoisomers thereof,wherein A, B, R₁, and R₂ are as defined above.

In a more specific embodiment of structure (VII), all occurrences of R₄,R_(4a), R₅ and R_(5a) are hydrogen, and the compounds of this inventionhave the following structure (VII′):

including pharmaceutically acceptable salts and stereoisomers thereof,wherein m, n, R₁, and R₂ are as defined above.

In a more specific embodiment of structure (VII′), m is 1, n is 1 andthe compounds of this invention have the following structure (VII″):

including pharmaceutically acceptable salts and stereoisomers thereof,wherein R₁ and R₂ are as defined above.

In a seventh embodiment structure (I), Y is —S—, the compounds of thisinvention have the following structure (VIII):

including pharmaceutically acceptable salts and stereoisomers thereof,wherein A, B, R₁ and R₂ are as defined above.

In a more specific embodiment of structure (VII), all occurrence of R₄,R_(4a), R₅ and R_(5a) are hydrogen, and the compound of this inventionhave the following structure (VIII′):

including pharmaceutically acceptable salts and stereoisomers thereof,wherein m, n, R₁ and R₂ are as defined above.

In a more specific embodiment of structure (VIII′), m is 1, n is 1 andthe compound of this invention have the following structure (VIII″):

including pharmaceutically acceptable salts and stereoisomers thereof,wherein R₁ and R₂ are as defined above.

As mentioned above, the helix mimetics of the present invention areuseful as bio-active agents, such as diagnostic, prophylactic, andtherapeutic agents. The helix mimetics were found to effectivelydisplace substance P in a calcium flux assay. The data thus indicate theability of helix mimetics to antagonize neurokinin-1 and serve aspotential therapy for central nervous system disorders and otherdisorders.

In this invention, libraries containing helix mimetics of the presentinvention are disclosed. Once assembled, the libraries of the presentinvention may be screened to identify individual members havingbioactivity. Such screening of the libraries for bioactive members mayinvolve, for example, evaluating the binding activity of the members ofthe library or evaluating the effect the library members have on afunctional assay. Screening is normally accomplished by contacting thelibrary members (or a subset of library members) with a target ofinterest, such as, for example, an antibody, enzyme, receptor or cellline. Library members which are capable of interacting with the targetof interest are referred to herein as “bioactive library members” or“bioactive mimetics.” For example, a bioactive mimetic may be a librarymember which is capable of binding to an antibody or receptor, which iscapable of inhibiting an enzyme, or which is capable of eliciting orantagonizing a functional response associated, for example, with a cellline. In other words, the screening of the libraries of the presentinvention determines which library members are capable of interactingwith one or more biological targets of interest. Furthermore, wheninteraction does occur, the bioactive mimetic (or mimetics) may then beidentified from the library members. The identification of a single (orlimited number) of bioactive mimetic(s) from the library yields helixmimetics which are themselves biologically active, and thus useful asdiagnostic, prophylactic or therapeutic agents, and may further be usedto significantly advance identification of lead compounds in thesefields.

Synthesis of the helix mimetics of the library of the present inventionmay be accomplished using known peptide synthesis techniques, incombination with the component pieces of this invention. Morespecifically, any amino acid sequence may be added as any of the R₁, R₂,R₃, R₄, R_(4a), R₅ or R_(5a) moieties of the helix mimetic. Preferablythe amino acid sequence may be added as the R₁ or R₃ moieties. To thisend, the mimetics may be synthesized on a solid support (such aspolystyrene utilizing 4-hydroxymethylphenoxybutyrate as a linker) byknown techniques (see, e.g., John M. Stewart and Janis D. Young, SolidPhase Peptide Synthesis, 1984, Pierce Chemical Comp., Rockford, Ill.;Atherton, E., Shepard, R. C. Solid Phase Peptide Synthesis: A PracticalApproach; IRL: Oxford, 1989) or on a silyl-linked resin by alcoholattachment (Randolph et al., J. Am. Chem. Soc. 117:5712-14, 1995). Theutility and ease of synthesis of the helix mimetic of the presentinvention is further exemplified by the applicability of wide variety ofcommercially available resins. To this end, core of either polystyreneor ArgoGel (polyethyleneglycol grafted polystyrene; Argonaut, SanCarlos, Calif.) utilizing aminomethyl polystyrene, benzhydrylamine (BHA)methylbenzhydrylamine (MBHA) (Matsueda et al., Peptides 2:45, 1981),phenoxybenzylalcohol (Wang resin) (Wang J. Am. Chem. Soc. 95:1328,1973), 2-clorotrytyl (Barlos et al., Tetrahedron Lett. 30:3943, 1989,ibid 30:3947, 1989), and PAL (Albericio et al., J. Org. Chem. 55:37301990) resins and other resins could be used in the synthesis of thepresent invention.

In addition, a combination of both solution and solid phase synthesistechniques may be utilized to synthesize the helix mimetics of thisinvention. For example, a solid support may be utilized to synthesizethe linear peptide sequence up to the point that the helix mimetic isadded to the sequence. A suitable conformationally constrained helixmimetic which has been previously synthesized by solution synthesistechniques may then be added as the next “amino acid” to the solid phasesynthesis (i.e., the helix mimetic, which has at least two reactivesites, may be utilized as the next residue to be added to the linearpeptide). Upon incorporation of the helix mimetic into the sequence,additional amino acids may then be added to complete the peptide boundto the solid support. Alternatively, the linear N-terminus andC-terminus protected peptide sequences may be synthesized on a solidsupport, removed from the support, and then coupled to the helix mimeticin solution using known solution coupling techniques.

In this regard, the helix mimetics of the present invention maygenerally be prepared by sequential coupling of the individual componentpieces either stepwise in solution or by solid phase synthesisillustrated in the following General Reaction Scheme. Such techniquesare further illustrated in the Examples.

In another aspect of this invention, methods for constructing librariesare disclosed. Traditional combinatorial chemistry (e.g., TheCombinatorial Index Bunin, Academic Press, New York, 1998; Gallop etal., J. Med. Chem. 37:1233-1251, 1994) and parallel synthesis techniquespermit a vast number of compounds to be rapidly prepared by thesequential combination of reagents to a basic molecular scaffold. Forexample, the above disclosed synthesis may be carried out using thedirected sorting technique of Nicolaou and coworkers. (Nicolaou et al.,Angew. Chem. Int'l. Ed. 34:2289-2291, 1995). Presently, equipment forthis technique is commercially available from IRORI (La Jolla, Calif.).Alternatively, the above disclosed synthesis may be carried out byparallel synthesis using a 48- or 96-well plate format wherein each wellcontains a fritted outlet for draining solvents and reagents (APractical Guide to Combinatorial Chemistry Czamik and DeWitt, Eds.,American Chemical Society, Washington, D.C., 1997). Robbins (Sunnyvale,Calif.), Charybdis (Carlsbad, Calif.) and Bohdan (Chicago, Ill.)presently offer suitable equipment for this technique.

In a further aspect of this invention, methods for screening librariesfor bioactivity and isolating bioactive library members are disclosed.The libraries of the present invention may be screened for bioactivityby a variety of techniques and methods. Generally, the screening assaymay be performed by (1) contacting a library with a biological target ofinterest, such as a receptor, and allowing binding to occur between themimetics of the library and the target, and (2) detecting the bindingevent by an appropriate assay, such as by the calorimetric assaydisclosed by Lam et al. (Nature 354:82-84, 1991) or Griminski et al.(Biotechnology 12:1008-1011, 1994). In a preferred embodiment, thelibrary members are in solution and the target is immobilized on a solidphase. Alternatively, the library may be immobilized on a solid phaseand may be probed by contacting it with the target in solution.

In another aspect, the present invention encompasses pharmaceuticalcompositions prepared for storage or administration which comprise atherapeutically effective amount of a compound of the present inventionin a pharmaceutically acceptable carrier or diluent. The“therapeutically effective amount” of a compound of the presentinvention will depend on the route of administration, the type ofwarm-blooded animal being treated, and the physical characteristics ofthe specific animal under consideration. These factors and theirrelationship to determining this amount are well known to skilledpractitioners in the medical arts. This amount and the method ofadministration can be tailored to achieve optimal efficacy but willdepend on such factors as weight, diet, concurrent medication and otherfactors, which those skilled in the medical arts will recognize.

The “therapeutically effective amount” of the compound of the presentinvention can range broadly depending upon the desired affects and thetherapeutic indication. Typically, dosages will be between about 0.01mg/kg and 100 mg/kg body weight, preferably between about 0.01 and 10mg/kg, body weight.

“Pharmaceutically acceptable carriers” for therapeutic use, includingdiluents, are well known in the pharmaceutical art, and are described,for example, in Remingtons Pharmaceutical Sciences, Mack Publishing Co.(Gennaro Ed. 1985). For example, sterile saline and phosphate-bufferedsaline at physiological pH may be used. Preservatives, stabilizers, dyesand even flavoring agents may be provided in the pharmaceuticalcomposition. For example, sodium benzoate, sorbic acid and esters ofp-hydroxybenzoic acid may be added as preservatives. In addition,antioxidants and suspending agents may be used.

The compounds of the present invention are useful in the prevention andtreatment of a wide variety of clinical conditions which arecharacterized by the presence of an excess tachykinin, in particularsubstance P, activity. These conditions may include disorders of thecentral nervous system such as anxiety, depression, psychosis andschizophrenia; epilepsy; neurodegenerative disorders such as dementia,including senile dementia of the Alzheimer type, Alzheimer's disease andDown's syndrome; demyclinating diseases such as multiple sclerosis (MS)and amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease) and otherneuropathological disorders such as peripheral neuropathy, or exampleAIDS related neuropathy, diabetic neuropathy, chemotherapy-inducedneuropathy, and other neuralgias; small cell carcinomas such as smallcell lung cancer; respiratory diseases, particularly those associatedwith excess mucus secretion, such as chronic obstructive airwaysdisease, bronchopneumonia, chronic bronchitis, acute bronchitis, diffusepanbronchilitis, emphysema, cystic fibrosis, asthma, and bronchospasm;airways disease modulated by neurogenic inflammation;laryngopharhngitis; bronchiectasis; conoisis; whooping cough; pulmonarytuberculosis; diseases associated with decreased glandular secretions,including lacrimation, such as Sjogren's syndrome, hyperlipoproteinemiasIV and V, hemochromatosis, sarcoidosis, or amyloidosis; iritis;inflammatory diseases such as inflammatory bowel disease, inflammatoryintestinal disease, psoriasis, fibrositis, ocular inflammation,osteoarthritis, rheumatoid arthritis, pruritis, and sunburn; hepatitis;allergies such eczema and rhinitis; hyper sensitivity disorders such aspoison ivy; ophthalmic diseases such a conjunctivitis, vernalconjunctivitis, dry eye syndrome, and the like; ophthalmic conditionsassociated with cell proliferation such as proliferativevitreoretinopathy; cutaneous diseases such as contact dermatitis, atopicdermatitis, urticaria, and other eczematoid dermatitis;hemodialysis-associated itching; lichen planus; oedema, such as oedemacaused by thermal injury; addiction disorders such as alcoholism; mentaldisease, particularly anxiety and depression; stress related somaticdisorders; reflex sympathetic dystrophy such as shoulder/hand syndrome;dysthymic disorders; tenalgia attended to hyperlipidemia; postoperativeneuroma, particularly of mastectomy; vulvar vestibulitis; amniogenesis;adverse immunological reactions such as rejection of transplantedtissues and disorders related to immune enhancement of suppression, suchas systemic lupus erythmatosus; gastrointestinal (GI) disorders,including inflammatory disorders, and disease of the GI tract, such asgastritis, gastroduodenal ulcers, gastric carcinomas, gastric lymphomas,disorders associated with the neuronal control of viscera such asulcerative colitis, Crohn's disease, irritable bowel syndrome, nausea,and emesis, including acute, delayed, post-operative, late-phase, andanticipatory emesis, such as emesis or nausea induced by for examplechemotherapy, radiation, surgery, migraine, toxins, such as metabolic ormicrobial toxins, viral or bacterial infections, pregnancy, vestibulardisorder, motion, mechanical stimulation, gastrointestinal obstruction,reduced gastrointestinal motility, visceral pain, psychological stressor disturbance, high altitude, weightlessness opioid analgesics,intoxication, resulting for example from consumption of alcohol, andvariations in intercranial pressure, in particular, for example, drug orradiation induced emesis or post-operative nausea and vomiting;disorders of bladder function such as cystitis, bladder detrusorhyperreflexia, and incontinence; fibrosing and collagen diseases such asscleroderma and eosinophilic fascioliasis; disorders of blood flowcaused by vasodilation and vasospastic diseases such as angina, migraineand Reynaud's disease; and pain of nociception, for example, chronicpain of that attributable to or associated with any of the foregoingconditions especially the transmission of pain in migraine, of such asheadache, toothache, cancerous pain, back pain, and superficial pain oncongelation, burn, herpes zoster of diabetic neuropathy. Hence, thesecompounds may be readily adapted to therapeutic use for the treatment ofphysiological disorders associated with an excessive stimulation oftachykinin receptors, especially neurokinin-1, and as neurokinin-1antagonists in the control and/or treatment of any of the aforesaidclinical conditions in mammals, including humans.

The compounds of the present invention are also of value in thetreatment of a combination of the above conditions, in particular in thetreatment of combined post-operative pain and post-operative nausea andvomiting.

The compounds of the present invention are particularly useful in thetreatment of nausea or emesis, including acute, delayed, post-operative,late-phase, and anticipatory emesis, such as emesis or nausea induced byfor example chemotherapy, radiation, surgery, migraine, toxins, such asmetabolic or microbial toxins, viral or bacterial infections, pregnancy,vestibular disorder, motion, mechanical stimulation, gastrointestinalobstruction, reduced gastrointestinal motility, visceral pain,psychological stress or disturbance, high altitude, weightlessness,opioid analgesics, intoxication, resulting for example from consumptionof alcohol, and variations in intercranial pressure. Most especially,this compounds is of use in the treatment of emesis induced byantineoplastic (cytotoxic) agents including those routinely used incancer chemotherapy.

Examples of such chemotherapeutic agents include alkylating agents, forexample, nitrogen mustards, ethyleneimine compounds, alkyl sulfonatesand other compounds with an alkylating action such as nitrosoureas,cisplatin, and dacarbazine; antimetabolites, for example, folic acid,purine or pyrimidine antagonists; mitotic inhibitors, for example, vincaalkaloids and derivatives of podophyllotoxin; and cytotoxic antibiotics.Particular examples of chemotherapeutic agents are described, forexample, by D. J. Stewart in “Nausea and Vomiting: Recent Research andClinical Advances,” Eds. J. Kucharczyk et al., CRC Press Inc., BocaRaton, Fla., USA (1991), pages 177-203. Commonly used chemotherapeuticagents include cisplatin, dacarbazine, mechlorethamine, streptozocin,cyclophosphamide, carmustine, lomustine, doxorubicin, daunorubicin,procarbazine, mitomycin, cytarabine, etoposide, methotrexate,5-fluorouracil, vinblastine, vincristine, bleomycin, and chlorambucil(Gralla et al., Cancer Treatment Reports 68, 163-172, 1984).

The compounds of the present invention are also of use in the treatmentof emesis induced by radiation including radiation therapy such as inthe treatment of cancer, or radiation sickness, and in the treatment ofpost-operative nausea and vomiting.

Further, the compounds of the present invention can act as calciumchannel blocking agents. As such, the compounds of the present inventionare useful in the prevention or treatment of clinical conditions whichbenefit from inhibition of the transfer of calcium ions across theplasma membrane of cells. These include diseases and disorders of theheart and vascular system such as angina pectoris, myocardialinfarction, cardiac arrhythmia, cardiac hypertrophy, cardiac vasospasm,hypertension, cerebrovascular spasm and other ischemic disease.Furthermore, these compounds may be capable of lowering elevatedintraocular pressure when administered topically to the hypertensive eyein solution in a suitable ophthalmic vehicle. Also, these compounds maybe useful in the reversal of multidrug resistance in tumor cells byenhancing the efficacy of chemotherapeutic agents. In addition, thecompounds may have activity in blocking calcium channels in insect brainmembranes and so may be useful as insecticides.

The compounds of the present invention are particularly useful in thetreatment of pain or nociception and/or inflammation and disordersassociated therewith such as, for example: neuropathy, such as diabeticor peripheral neuropathy and chemotherapy-induced neuropathy;postherpetic and other neuralgias; asthma; osteoarthritis; rheumatoidarthritis; and migraine. The compounds of the present invention are alsoparticularly useful in the treatment of diseases characterized byneurogenic mucus secretion, especially cystic fibrosis.

The compounds of this invention may be administered by inhalation, andthus may be delivered in the form of an aerosol spray from pressurizedpacks or nebulizers. The compounds may also be delivered as powderswhich may be formulated and the powder composition may be inhaled withthe aid of an insufflation powder inhaler device. A preferred deliverysystem for inhalation is the metered dose inhalation aerosol, which maybe formulated as a suspension or solution of a compound of the inventionin suitable propellants, such as fluorocarbons or hydrocarbons. Anotherpreferred delivery system is the dry powder inhalation aerosol, whichmay be formulated as a dry powder of a compound of this invention withor without additional excipients.

The compounds of the invention can be administered in the form of adepot injection or implant preparation which may be formulated in such amanner as to permit a sustained release of the active ingredient. Theactive ingredient can be compressed into pellets or small cylinders andimplanted subcutaneously or intramuscularly as depot injections orimplants. Implants may employ inert materials such as biodegradablepolymers or synthetic silicones, for example, Silastic, silicone rubberor other polymers manufactured by the Dow-Corning Corporation.

The compounds of the invention can also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom a variety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

The compounds of this invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The neurokinin inhibitors may also be coupledwith soluble polymers as targetable drug carriers. Such polymers caninclude polyvinlypyrrolidone, pyran copolymer,polyhydroxy-propyl-methacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the neurokinininhibitors may be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example, polylactic acid,polyglycolic acid, copolymers of polylactic and polyglycolic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross linked oramphipathic block copolymers of hydrogels.

The pharmaceutical compositions of this invention may be used in theform of a pharmaceutical preparation, for example in solid, semisolid orliquid form, which contains one or more of the compounds of the presentinvention, as an active ingredient, in admixture with an organic orinorganic carrier or excipient suitable for external, enteral orparenteral applications. The active ingredient may be compounded, forexample, with the usual non-toxic, pharmaceutically acceptable carriersfor tablets, pellets, capsules, suppositories, solutions, emulsions,suspensions, and any other form suitable for use. The carriers which canbe used are water, glucose, lactose, gum acacia, gelatin, mannitol,starch paste, magnesium trisilicate, talc, corn starch, keratin,colloidal silica, potato starch, urea and other carriers suitable foruse in manufacturing preparation, in solid, semisolid, or liquid form,and in addition auxiliary, stabilizing, thickening and coloring agentsand perfumes may be used. The active object compounds is included in thepharmaceutical composition in an amount sufficient to produce thedesired effect upon the process or condition of the disease.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier; conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents; water, to from a solid preformulationcomposition containing homogeneous mixture of a compound of the presentinvention, or a non-toxic pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective unit dosage forms such as tablets, pills and capsules.This solid preformulation composition is then subdivided into unitdosage forms of the type, described above containing from about 0.1 toabout 500 mg of the active ingredient of the present invention. Thetablets or pills of the novel composition can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permits theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layerscoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, acetylalcohol and cellulose acetate.

The liquid forms in which the compositions of the present invention maybe incorporated for administration orally or by injection includeaqueous solution, suitably flavored syrups, aqueous or oil suspensions,and emulsions with acceptable oils such as cottonseed oil, sesame oil,coconut oil or peanut oil, or with solubilizing or emulsifying agentsuitable for intravenous use, as well as elixirs and similarpharmaceutical vehicics. Suitable dispersing or suspending agents foraqueous suspensions include synthetic and natural gums such astragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone or gelatin.

For the treatment of the clinical conditions and diseases noted above,the compounds of this invention may be administered orally, topically,parenterally, by inhalation spray or rectally in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques.

For the treatment of certain conditions it may be desirable to employ acompound of the present invention in conjunction with anotherpharmacologically active agent. For example, a compound of the presentinvention may be presented together with another therapeutic agent as acombined preparation for simultaneous, separate, or sequential use forthe relief of emesis. Such combined preparations may be, for example, inthe form of a twin pack. A preferred combination comprises a compound ofthe present invention with a chemotherapeutic agent such as analkylating agent, antimetabolite, mitotic inhibitor, or cytotoxicantibiotic, as described above. In general, the currently availabledosage forms of the known therapeutic agents for use in suchcombinations will be suitable.

Similarly, for the treatment of respiratory diseases, such as asthma, acompound of the present invention may be used in conjunction with abronchodilator, such as a β₂-adrenergic receptor agonist of a tachykininantagonist which acts at neurokinin-2 receptors. Also, for the treatmentof conditions that require antagonism of both neurokinin-1 andneurokinin-2, including disorders associated with bronchoconstrictionand/or plasma extravasation in airways, such as asthma, chronicbronchitis, airways disease, or cystic fibrosis, a compound of thepresent invention may be used in conjunction with a tachykininantagonist which acts at neurokinin-2 receptors, or with tachykininreceptor antagonist which acts at neurokinin-1, neurokinin-2, andneurokinin-3 receptors. Similarly, for the prevention of treatment ofemesis a compound of the present invention may be used in conjunctionwith other anti-emetic agents, especially 5HT₃ receptor antagonists,such as ondansetron, granisetron, tropisetron, decadron, zatisetron, aswell as other commercially and naturally available pharmacologicallyactive agents. Likewise, for the prevention or treatment of migraine acompound of the present invention may be used in conjunction with otheranti-migraine agents, such as ergotamines or 5HT₃ agonists, especiallysumatriptan. Likewise, for the treatment of behavioral hyperalgesia, acompound of the present invention may be used in conjunction with anantagonist of N-methyl D-asparatate (NMDA), such as dizocilpine. For theprevention of treatment of inflammatory conditions in the lower urinarytract, especially cystitis, a compound of the present invention may beused in conjunction with an antiinflammatory agent, such as a bradykininreceptor antagonist. The compound of the present invention and the otherpharmacologically active agent may be administered to a patientsimultaneously, sequentially or in combination.

The compounds of this invention may be administered to patients (animalsand humans) in need of such treatment in dosages that will provideoptimal pharmaceutical efficacy. It will be appreciated that the doserequired for use in any particular application will vary from patient topatient, not only with the particular compound or composition selected,but also with the route of administration, the nature of the conditionbeing treated, the age and condition of the patient, concurrentmedication of special diets then being followed by patient, and otherfactors which those skilled in the art will recognize, with theappropriate dosage ultimately being at the discretion of the attendantphysician.

In the treatment of a condition associated with an excess oftachykinins, an appropriate dosage level will generally be about 0.001to about 50 mg per kg patient body weight per day which may beadministered in single or multiple doses. Preferably, the dosage levelwill be about 0.01 to about 25 mg/kg per day; more preferably about 0.05to about 10 mg/kg per day. For example, in the treatment of conditionsinvolving the neurotransmission of pain sensations, a suitable dosagelevel is about 0.001 to about 25 mg/kg per day, preferably about 0.05 toabout 10 mg/kg per day, and especially about 0.1 to about 5 mg/kg perday. A compound may be administered on a regimen of 1 to 4 times perday, preferably once or twice per day. In the treatment of emesis usingan injectable formulation, a suitable dosage level is about 0.001 toabout 10 mg/kg per day, preferably about 0.005 to about 5 mg/kg per day,and especially about 0.05 to about 5 mg/kg per day, A compound may beadministered on a regiment of 1 to 4 times per day, preferably once ortwice per day.

The dose and method of administration can be tailored to achieve optimalefficacy but will depend on such factors as weight, diet, concurrentmedication and other factors which those skilled in the medical artswill recognize. When administration is to be parenteral, such asintravenous on a daily basis, injectable pharmaceutical compositions canbe prepared in conventional forms, either as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions.

The following examples are provided for purposes of illustration, notlimitation. These examples illustrate the syntheses of helix mimetics ofthis invention. Specifically, the preparation of helix mimetics wascarried out on solid phase. The solid phase syntheses of these helixmimetics demonstrate that libraries containing such members may bereadily prepared.

TABLE 2 Abbreviations used in Examples Reagents: AcOH acetic acid BOPbenzotriazol-1-yloxy-tris(dimethylamino)phos- phoniumhexafluorophosphate DIAD diisoproppyl azodicarboxylate DIC diisopropylcarbonyl diimide DIEA N,N-diisopropylethylamine HATUO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl- uroniumhexafluorophosphate HOAt 1-hydroxy-7-azabenzotriazole HOBt1-hydroxybenzotriazole hydrate MCPBA 3-chloroperoxybenzoic acid PyBOPbenzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphateTFA trifluoroacetic acid TPP triphenylphosphine Solvents: DCMdichloromethane DMF dimethylformamide DMSO dimethylsulfoxide Et₂Odiethyl ether MeOH methanol THF tetrahydrofuran Protecting Groups: Allallyl Alloc allyloxy carbonyl Fmoc 9-fluorenylmethoxy carbonyl tButyltertiary-Butyl Trt triphenylmethyl Others: Dess-Martin Dess-Martinperiodinane LC/MS HPLC/Mass spectrometry rt room temperature

The reactions were carried out in but not limited to the following:plastic disposable syringes of the appropriate size, each fitted with apolypropylene frit to retain the resin, 1-10 ml reaction vesselcompatible with Symphony Automated Peptide Synthesizer (ProteinTechnologies), ACT 90 Synthesizer (Advanced ChemTech), Robbins block, orIRORI system.

LCMS analysis was performed on reverse-phase C₁₈ Zorbax columns usingthe following solvent system: A, water with 0.1% formic acid; B,acetonitrile with 0.1% formic acid. The following conditions wereapplied: column 2.1×30 mm, 5-95% B in 3 min (for compounds of Tables 3and 4) or 4 min (for compounds of Table 5), flow 0.8 ml/min. Massspectra for separated peaks were obtained by electrospray (ES) using aMicroMass LCZ mass spectrometer.

EXAMPLES

These examples illustrate the synthesis of representative helix mimeticsof this invention. The solid phase syntheses of these helix mimeticsdemonstrate that libraries containing such members may be readilyprepared. Structures of representative helix mimetics are given in Table3, 4 and 5.

Example 1 Solid Phase Syntheses of Representative Helix Mimetic

Commercially available 2-bromo-1-ethoxy-1-oxy-polystyrene resin(Pol-O-CH(OEt)-CH₂Br) (Advanced ChemTech) was suspended in DMSO to whichan amine (10 equivalents) was added. The resulting mixture wasmechanically stirred using an overhead stirrer and heated to 60° C.After 24 h, the resin was filtered and washed sequentially with DMSO,DMF, MeOH, DMF, MeOH, Et₂O then dried in vacuo. The substitution of theresin was determined spectroscopically by the Fmoc release method.

The secondary amine resin resin (Pol-O—CH(OEt)-CH₂—NH—R₁) was contactedwith a 0.05 N solution of α-N-Fmoc-γ-O-allyl-aspartic acid(Fmoc-Asp(OAll)OH), HATU and DIEA in DMF (4 equivalents). The resultingmixture was agitated for 2 h then tested against chloranil/vacetaldehydefor complete reaction. Upon a negative chloranil test, the resin wasfiltered, sequentially washed with DMF, MeOH, DMF, MeOH. The Fmoccarbamate was deprotected by contacting the resin with 25%piperidine/DMF at room temperature. Following 1 h, the resin wasdrained, and washed sequentially with DMF, MeOH, DMF, MeOH, Et₂O anddried in vacuo.

Method A1

The deprotected resin(Pol-O—CH(OEt)-CH₂—N—(R₁—CO—CH—(CH₂CO₂CH₂CH═CH₂)—NH₂) was contacted witha 0.04 N solution of the carboxylic acid (R2), PyBop, HOBt and DIEA inDMF (3 equivalents). The reaction was tested for completeness using theKaiser ninhydrin test after 1 h. Once the reaction was found to becomplete, the resin was drained, and sequentially washed with DMF, MeOH,DMF, MeOH and Et₂O then dried in vacuo.

Method A2

The deprotected resin(Pol-O—CH(OEt)-CH₂—N—(R₁)—CO—CH—(CH₂CO₂CH₂CH═CH₂)—NH₂) was contactedwith a 0.04 N solution of a N-hydroxysuccinimyl carbonate (R2) in DMF (3equivalents). After 2 h the reaction was checked for completeness usingthe Kaiser ninhydrin test. Once the reaction was found to be complete,the resin was drained and washed sequentially with DMF, MeOH, DMF, MeOHand Et₂O then dried in vacuo

Method A3

The deprotected resin(Pol-O—CH(OEt)-CH₂—N—(R₁)—CO—CH—(CH₂CO₂CH₂CH═CH₂)—NH₂) was contactedwith a 0.04 N solution of an isocyanate (R2) in DMF (3 equivalents).After 2 h the reaction was checked for completeness using the Kaiserninhydrin test. Once the reaction was found to be complete, the resinwas drained and washed sequentially with DMF, MeOH, DMF, MeOH and Et₂Othen dried in vacuo.

Method A4

The deprotected resin(Pol-O—CH(OEt)-CH₂—N—(R₁)—CO—CH—(CH₂CO₂CH₂CH═CH₂)—NH₂) was contactedwith a 0.05 N solution of sulphonyl chloride (R2) and N-methylmorpholinein DCM (4 equivalents). After 2 h the reaction was checked forcompleteness using the Kaiser ninhydrin test. Once the reaction wasfound to be complete, the resin was drained and washed sequentially withDCM, MeOH, DCM, MeOH and Et₂O then dried in vacuo.

Allyl Deprotection

The allyl ester resin resulting from Method A1-A4 was deprotected bycontacting with a solution of 0.02 N (Ph₃P)₄Pd⁰, Ph₃P and 0.20 N PhSiH₃in DCM for 2 h. The resin was then filtered and washed sequentially withDCM (2×), MeOH, DCM, MeOH and DCM then dried in vacuo.

The resin containing the y-carboxylic acid(Pol-O—CH(OEt)-CH₂—N(R₁)—CO—CH—(CH₂CO₂H)—NHR₂) was contacted with a 0.04N solution containing an amine (R₃—NH₂), PyBop, HOBt, and DIEA in DMF (3equivalents). After 4 h, the resin was drained and washed sequentiallywith DMF, MeOH, DMF, MeOH and Et₂O, then dried in vacuo.

The resin resulting from the above method(Pol-O—CH(OEt)-CH₂—N—(R₁)—CO—CH—CH₂CONHR₃)—NHR₂) was swelled with DCMthen contacted with glacial formic acid (approximately 2 mL/50 mg resin)for 14 h. The resulting solution was drained and the resin washed with10% (v/v) formic acid/DCM (0.5 mL/50 mg resin). The combined solutionswere evaporated in vacuo. The residue was dissolved in 50% (v/v) aqueoussolution of acetonitrile, frozen to −76° C. and lyopholized.

Example 2 Synthesis of Representative Helix Mimetic

The representative compounds listed in Table 3 were synthesizedaccording to the procedures set forth in Example 1.

TABLE 3 Representative Compounds of Structure Type (II″)

Cpd R1 R2 R3 Method LC RT M + H⁺ 1

A1 1.57 607.3 2

A3 1.34 395.2 3

A4 0.75 583.3 4

A1 1.78 578.2 5

A3 1.33 512.4 6

A2 0.97 470.2 7

A3 1.04 419.3 8

A3 1.45 532.3 9

A4 0.97 600.3 10

A2 1.49 518.2 11

A1 1.06 498.3 12

A4 0.84 533.2 13

A3 1.36 470.3 14

A3 1.01 483.2 15

A4 1.8 482.2 16

A1 1.96 653.3 17

A2 0.84 503.2 18

A3 0.87 543.4 19

A3 1.5 498.3 20

A1 0.74 486.3 21

A4 1.65 500.2 22

A3 1.57 488.3 23

A1 1.36 482.3 24

A2 0.97 553.2 25

A1 0.27 484.3 26

A1 2.02 636.5 27

A1 1.47 658.3 28

A4 1.15 479.5 29

A2 1.49 484.5 30

A1 2.05 602.5

Example 3 Synthesis of Representative Helix Mimetic

Commercially available 2-bromo-1-ethoxy-1-oxy-polystyrene resin(Pol-O—CH(OEt)-CH2—Br) (Advanced ChemTech) was suspended in DMSO towhich an amine, R₁NH₂, (10 equivalents) was added. The resulting mixturewas mechanically stirred using an overhead stirrer and heated to 60° C.After 24 h, the resin was filtered and washed sequentially with DMSO,DMF, MeOH, DMF, MeOH, and Et₂O then dried in vacuo. The substitution ofthe resin was determined spectroscopically by the Fmoc release method.

The secondary amine resin (Pol-O—CH(OEt)-CH₂—NHR₁) was contacted with a0.05 N solution of α-Fmoc-β-Alloc-2,4-diamanobutyric acid(Fmoc-Dab(Alloc)OH), HATU and DIEA in DMF (4 equivalents). The resultingmixture was agitated for 2 h then tested against chloranil/acetaldehydefor complete reaction. Upon a negative chloranil test, the resin wasfiltered, sequentially washed with DMF, MeOH, DMF and MeOH. The Fmoc wasdeprotected by contacting the resin with 25% piperidine/DMF at roomtemperature. Following 1 h, the resin was drained, and washedsequentially with DMF, MeOH, DMF, MeOH and Et₂O and dried in vacuo.

Method A1

The deprotected Alloc-resin(Pol-O—CH(OEt)-CH₂—NR₁—C(═O)—CH(CH₂CH₂NH—Alloc)—NH₂) was contacted withcarboxylic acid (R₂CO₂H) and treated as previously described.

Method A2

The deprotected Alloc-resin(Pol-O—CH(OEt)-CH₂—NR₁—C(═O)—CH(CH₂CH₂NH—Alloc)—NH₂) was contacted withN-hydroxysuccinimyl carbonate (R₂CO₂Su) and treated as previouslydescribed.

Method A3

The deprotected Alloc-resin(Pol-O—CH(OEt)-CH₂—NR₁—C(═O)—CH(CH₂CH₂NH—Alloc)—NH₂) was contacted withan isocyanate (R₂NCO) and treated as previously described.

Method A4

The deprotected Alloc-resin(Pol-O—CH(OEt)-CH₂—NR₁—C(═O)—CH(CH₂CH₂NH-Alloc)—NH₂) was contacted witha solution of sulphonyl chloride (R₂SO₂Cl) and treated as previouslydescribed.

Alloc Deprotection

The Alloc carbamate resin resulting from Method A1-A4 was deprotected bycontacting with a solution of 0.02 N (Ph₃P)₄Pd⁰, Ph₃P and 0.20 N PhSiH₃in DCM for 2 h. The resin was then filtered and washed sequentially withDCM (2×), MeOH, DCM, MeOH and DCM then dried in vacuo.

Method B1

The Alloc deprotected resin(Pol-O—CH(OEt)-CH₂—NR₁—C(═O)—CH(CH₂CH₂NH₂)—NH₂) was contacted with a0.04 N solution of the carboxylic acid (R₃CO₂H), PyBop, HOBt and DIEA inDMF (3 equivalents). The reaction was tested for completeness using theKaiser ninhydrin test after 1h. Once the reaction was found to becomplete, the resin was drained, and sequentially washed with DMF, MeOH,DMF, MeOH and Et₂O then dried in vacuo.

Method B2

The Alloc deprotected resin(Pol-O—CH(OEt)-CH₂—NR₁—C(═O)—CH(CH₂CH₂NH₂)—NH₂) was contacted with a0.04 N solution of a N-hydroxysuccinimyl carbonate (R₃CO₂SU) in DMF (3equivalents). After 2 h the reaction was checked for completeness usingthe Kaiser ninhydrin test. Once the reaction was found to be complete,the resin was drained and washed sequentially with DMF, MeOH, DMF, MeOHand Et₂O then dried in vacuo.

Method B3

The Alloc deprotected resin(Pol-O—CH(OEt)-CH₂—NR₁—C(═O)—CH(CH₂CH₂NH₂)—NH₂) was contacted with a0.04 N solution of an isocyanate (R₃NCO) in DMF (3 equivalents). After 2h the reaction was checked for completeness using the Kaiser ninhydrintest. Once the reaction was found to be complete, the resin was drainedand washed sequentially with DMF, MeOH, DMF, MeOH and Et₂O then dried invacuo.

Method B4

The Alloc deprotected resin(Pol-O—CH(OEt)-CH₂—NR₁—C(═O)—CH(CH₂CH₂NH₂)—NH₂) was contacted with a0.05 N solution of sulphonyl chloride (R₃SO₂Cl) and N-methylmorpholinein DCM (4 equivalents). After 2 h the reaction was checked forcompleteness using the Kaiser ninhydrin test. Once the reaction wasfound to be complete, the resin was drained and washed sequentially withDCM, MeOH, DCM, MeOH and Et₂O then dried in vacuo.

The resin resulting from Methods B1-B4 was swelled with DCM thencontacted with glacial formic acid (approximately 2 mL/50 mg resin) for14 h. The resulting solution was drained and the resin washed with 10%(v/v) formic acid/DCM (0.5 mL/50 mg resin). The combined solutions wereevaporated in vacuo. The residue was dissolved in 50% (v/v) aqueoussolution of acetonitrile, frozen to −76° C. and lyopholized.

Example 4 Synthesis of Representative Helix Mimetic

The representative compounds listed in Table 4 were synthesizedaccording to the procedures set forth in Example 3.

TABLE 4 Representative Compounds of Structure Type (III″) (III″)

LC M + Cpd R1 R2 R3 Method RT H⁺ 31

A1, B1 0.59 488.5 32

A1, B2 1.82 664.4 33

A1, B1 0.76 472.5 34

A1, B1 2.2 748.4 35

A2, B2 2.82 446.5 36

A1, B3 0.89 460.5 37

A3, B1 1.85 647.4 38

A2, B2 1.64 418.4 39

A2, B2 1.71 574.5 40

A2, B2 1.86 446.5 41

A1, B2 0.63 454.5 42

A1, B3 1.89 661.5 43

A1, B3 1.84 478.5 44

A1, B1 0.41 440.5 45

A1, B2 1.37 528.4 46

A1, B2 2.02 614.4 47

A2, B1 1.74 468.4 48

A1, B4 1.87 706.4 49

A2, B1 0.11 674.5 50

A1, B3 1.4 527.5 51

A1, B1 0.04 706.5 52

A1, B1 2.2 782.4 53

A1, B2 1.76 512.5 54

A1, B3 1.71 663.4 55

A2, B2 1.68 506.5 56

A3, B1 1.71 663.4 57

A3, B2 1.53 539.5 58

A2, B2 1.51 478.5 59

A1, B2 1.31 418.4 60

A2, B2 1.82 480.4 61

A3, B1 1.69 615.4 62

A2, B1 1.81 664.4 63

A1, B2 1.97 659.4 64

A1, B2 1.99 648.4 65

A2, B1 0.82 516.6 66

A1, B2 1 509.5 67

A1, B1 2.1 643.5 68

A2, B2 1.71 619.4 69

A2, B3 1.36 509.4 70

A3, B2 1.64 479.5 71

A1, B2 1.91 708.4 72

A1, B1 1.94 646.4 73

A1, B3 1.38 670.5 74

A2, B1 1.58 687.5 75

A1, B2 1.99 693.4 76

A1, B2 1.86 616.4 77

A1, B2 1.79 661.4 78

A1, B3 1.72 615.4 79

A1, B3 1.86 647.4 80

A2, B3 0.93 566.5 81

A1, B1 1.79 614.4 82

A2, B1 1.99 648.4 83

A1, B2 2.04 614.4 84

A1, B1 1.21 595.5 85

A2, B2 1.85 480.4 86

A1, B2 1.48 542.2 87

A2, B1 1.42 528.4 88

A3, B2 1.56 573.5 89

A1, B2 1.14 538.5 90

A1, B1 1.98 612.5 91

A2, B3 1.66 587.5 92

A1, B3 1.68 707.5 93

A1, B2 1.84 674.5 94

A1, B3 1.52 571.5 95

A2, B2 1.25 528.4 96

A1, B1 1.18 491.5 97

A2, B2 1.82 514.4 98

A3, B2 1.36 511.5 99

A1, B1 1.61 805.5 100

A1, B1 1.8 662.4 101

A2, B2 1.6 527.4 102

A2, B1 1.82 616.4 103

A3, B1 1.89 613.5 104

A1, B2 1.57 671.5 105

A1, B1 1.2 595.5 106

A2, B1 1.82 582.4 107

A2, B2 1.32 556.4 108

A1, B3 1.89 613.5 109

A1, B1 2.02 614.4 110

A1, B3 1.93 627.5 111

A1, B4 1.81 766.4 112

A3, B2 1.48 451.4 113

A1, B4 1.16 593.5 114

A1, B2 1.87 753.4 115

A1, B1 1.93 669.5 116

A1, B4 1.32 729.4 117

A2, B2 1.34 503.5 118

A1, B2 1.79 709.4 119

A1, B3 1.73 629.5 120

A1, B3 1.81 721.5 121

A1, B2 0.86 459.5 122

A1, B1 2.03 580.5 123

A1, B1 1.16 491.5 124

A1, B1 2.07 612.5 125

A3, B1 1.09 458.5 126

A2, B2 1.42 496.4 127

A1, B4 1.91 672.4 128

A1, B1 1.79 614.4 129

A2, B1 1.91 708.4 130

A1, B1 1.42 669.5 131

A1, B2 0.17 561.5 132

A1, B1 1.06 650.7 133

A1, B1 0.17 438.6 134

A2, B1 1.09 493.4 135

A2, B1 1.1 459.4

Example 5 Synthesis of Representative Helix Mimetic

Commercially available 2-bromo-1-ethoxy-1-oxy-polystyrene resin(Pol-O—CH(OEt)-CH2—Br) (Advanced ChemTech) was suspended in DMSO towhich an amine, R₁NH₂, (10 equivalents) was added. The resulting mixturewas mechanically stirred using an overhead stirrer and heated to 60° C.After 24 h, the resin was filtered and washed sequentially with DMSO,DMF, MeOH, DMF, MeOH, and Et₂O then dried in vacuo. The substitution ofthe resin was determined spectroscopically by the Fmoc release method.

The secondary amine resin (Pol-O—CH(OEt)-CH₂—NHR₁) was contacted with a0.05 N solution of α-Fmoc—S—Trt-Cystein (Fmoc-Cys(Trt)-OH), HATU andDIEA in DMF (4 equivalents). The resulting mixture was agitated for 2 hthen tested against chloranl/acetaldehyde for complete reaction. Upon anegative chloranil test, the resin was filtered, sequentially washedwith DMF, MeOH, DMF and MeOH. The Fmoc was deprotected by contacting theresin with 25% piperidine/DMF at room temperature. Following 1 h, theresin was drained, and washed sequentially with DMF, MeOH, DMF, MeOH andEt₂O and dried in vacuo.

Method C1

The deprotected resin (Pol-O—CH(OEt)-CH₂—NR₁—C(═O)—CH(CH₂S-Trt)-NH₂) wascontacted with carboxylic acid (R₂CO₂H) and treated as previouslydescribed.

Method C2

The deprotected resin (Pol-O—CH(OEt)-CH₂—NR₁—C(═O)—CH(CH₂S-Trt)-NH₂) wascontacted with N-hydroxysuccinimyl carbonate (R₂CO₂Su) and treated aspreviously described.

Method C3

The deprotected resin (Pol-O—CH(OEt)-CH₂—NR₁—C(═O)—CH(CH₂S-Trt)-NH₂) wascontacted with isocyanate (R₂NCO) and treated as previously described.

Method C4

The deprotected resin (Pol-O—CH(OEt)-CH₂—NR₁—C(═O)—CH(CH₂S-Trt)-NH₂) wascontacted with sulphonyl chloride (R₂SO₂Cl) and treated as previouslydescribed.

The resin resulting from Methods C1-C4 was swelled with DCM thencontacted with glacial formic acid (approximately 2 mL/50 mg resin) for14 h. The resulting solution was drained and the resin washed withformic acid (0.5 mL/50 mg resin). The combined solutions were evaporatedin vacuo. The residue was dissolved in acetic acid, frozen to −76° C.and lyopholized.

Example 6 Synthesis of Representative Helix Mimetic

Compound products from Example 5 were dissolved in DCM to which oneequivalent of mCPBA was added. The resulting solution was stirred for 10minutes at room temperature then passed through neutral Al₂O₃. Theproduct was eluted with 5% MeOH in DCM.

Example 7 Synthesis of Representative Helix Mimetic

Compound products from Example 5 were dissolved in DCM to which anexcess of mCPBA (3 to 5 eq.) was added. The resulting mixture wasstirred for 1 h at r.t. and then stored overnight at −20° C. Theresulting solution was filtered through a column of neutral Al₂O₃eluting with 5% MeOH in DCM to obtain the product.

Example 8 Synthesis of Representative Helix Mimetic

Commercially available 2-bromo-1-ethoxy-1-oxy-polystyrene resin(Pol-O—CH(OEt)-CH2—Br) (Advanced ChemTech) was suspended in DMSO towhich an amine, R₁NH₂, (10 equivalents) was added. The resulting mixturewas mechanically stirred using an overhead stirrer and heated to 60° C.After 24 h, the resin was filtered and washed sequentially with DMSO,DMF, MeOH, DMF, MeOH, and Et2O then dried in vacuo. The substitution ofthe resin was determined spectroscopically by the Fmoc release method.

The secondary amine resin (Pol-O—CH(OEt)-CH₂—NHR₁) was contacted with a0.05 N solution of α-Fmoc—O-tert-Butyl—Serine (Fmoc-Ser(t-Butyl)—OH),HATU and DIEA in DMF (4 equivalents). The resulting mixture was agitatedfor 2 h then tested against chloranil/acetaldehyde for completereaction. Upon a negative chloranil test, the resin was filtered,sequentially washed with DMF, MeOH, DMF and MeOH. The Fmoc wasdeprotected by contacting the resin with 25% piperidine/DMF at roomtemperature. Following 1 h, the resin was drained, and washedsequentially with DMF, MeOH, DMF, MeOH and Et₂O and dried in vacuo.

Method D1

The deprotected resin (Pol-O—CH(OEt)-CH₂—NR₁—C(═O)—CH(CH₂O-tButyl)-NH₂)was contacted with carboxylic acid (R₂CO₂H) and treated as previouslydescribed.

Method D2

The deprotected resin (Pol-O—CH(OEt)-CH₂—NR₁—C(═O)—CH(CH₂O-tButyl)-NH₂)was contacted with N-hydroxysuccinimyl carbonate (R₂CO₂Su) and treatedas previously described.

Method D3

The deprotected resin (Pol-O—CH(OEt)-CH₂—NR₁—C(═O)—CH(CH₂O-tButyl)-NH₂)was contacted with isocyanate (R₂NCO) and treated as previouslydescribed.

Method D4

The deprotected resin (Pol-O—CH(OEt)-CH₂—NR₁—C(═O)—CH(CH₂O-tButyl)-NH₂)was contacted with sulphonyl chloride (R₂SO₂Cl) and treated aspreviously described.

The resin resulting from Method D1-D4 was swelled with DCM thencontacted with glacial formic acid (approximately 2 mL/50 mg resin) for14 h. The resulting solution was drained and the resin washed withformic acid (0.5 mL/50 mg resin). The combined solutions were evaporatedin vacuo. The residue was dissolved in acetic acid, frozen to −76° C.and lyopholized.

Example 9 Synthesis of Representative Helix Mimetic

Commercially available 2-bromo-1-ethoxy-1-oxy-polystyrene resin(Pol-O—CH(OEt)CH2—Br) (Advanced ChemTech) was suspended in DMSO to whichan amine, R₁NH₂, (10 equivalents) was added. The resulting mixture wasmechanically stirred using an overhead stirrer and heated to 60° C.After 24 h, the resin was filtered and washed sequentially with DMSO,DMF, MeOH, DMF, MeOH, and Et₂O then dried in vacuo. The substitution ofthe resin was determined spectroscopically by the Fmoc release method.

The secondary amine resin (Pol-O—CH(OEt)-CH₂—NHR₁) was contacted with a0.05 N solution of α-Fmoc-O-tert-Butyl-Aspartic Acid(Fmoc-Asp(t-Butyl)-OH), HATU and DIEA in DMF (4 equivalents). Theresulting mixture was agitated for 2 h then tested againstchloranil/acetaldehyde for complete reaction. Upon a negative chloraniltest, the resin was filtered, sequentially washed with DMF, MeOH, DMFand MeOH. The Fmoc was deprotected by contacting the resin with 25%piperidine/DMF at room temperature. Following 1 h, the resin wasdrained, and washed sequentially with DMF, MeOH, DMF, MeOH and Et₂O anddried in vacuo.

Method E1

The deprotected resin(Pol-O—CH(OEt)-CH₂—NR₁—C(═O)—CH(CH₂CO₂-tButyl)—NH₂) was contacted withcarboxylic acid (R₂CO₂H) and treated as previously described.

Method E2

The deprotected resin(Pol-O—CH(OEt)-CH₂—NR₁—C(═O)—CH(CH₂CO₂-tButyl)—NH₂) was contacted withN-hydroxysuccinimyl carbonate (R₂CO₂Su) and treated as previouslydescribed.

Method E3

The deprotected resin(Pol-O—CH(OEt)-CH₂—NR₁—C(═O)—CH(CH₂CO₂-tButyl)—NH₂) was contacted withisocyanate (R₂NCO) and treated as previously described.

Method E4

The deprotected resin(Pol-O—CH(OEt)-CH₂—NR₁—C(═O)—CH(CH₂CO₂-tButyl)—NH₂) was contacted withsulphonyl chloride (R₂SO₂Cl) and treated as previously described.

The resin resulting from Method E1-E4 was swelled with DCM thencontacted with glacial formic acid (approximately 2 mL/50 mg resin) for14 h. The resulting solution was drained and the resin washed withformic acid (0.5 mL/50 mg resin). The combined solutions were evaporatedin vacuo. The residue was dissolved in acetic acid, frozen to −76° C.and lyopholized.

Example 10 Synthesis of Representative Helix Mimetic

The representative compounds listed in Table 5 were synthesizedaccording to the above procedures.

TABLE 5 Representative Compounds of Structure Type (IV″-VIII″)(IV″-VIII″)

Cpd R1 R2 Z Method LC RT M + H⁺ 136

C3 1.98 400.4 137

C4 1 398.4 138

C2 1.15 392.4 139

C1 1.08 390.4 140

C4 2.02 393.4 141

C2 2.18 387.4 142

C1 2.05 385.4 143

C4 2.14 423.36 144

C4, C5 1.78 439.3 145

C4, C5 1.78 409.3 146

C4, C6 1.99 425.3 147

C4, C6 2.14 455.3 148

D4 1.92 377.2 149

E1 1.88 397.4 150

E2 1.97 399.4 151

E3 1.71 384.4 152

E4 1.77 405.3 153

C2 1.61 438.4

Example 11 Tachykinin Antagonism Assay of Representative Compounds

The compounds of this inventions are useful for antagonizingtachykinins, in particular substance P in the treatment of inflammatorydiseases, central nervous system disorders, gastrointestinal disorders,pain or migraine and asthma in a mammal in need of such treatment. Thisactivity can be demonstrated by the following assay.

An assay measuring the ability of Compounds 1-153 to antagonize bindingof substance P peptide to its receptor neurokinin-1 was performed.Substance P is known to act upon cells via the mobilization of calcium(Bordey et al., Glia 11: 277-283, 1994). The compounds were assessed fortheir ability to inhibit the action of Substance P with the use of aFluorcscent Imaging Plate Reader (FLIPR) from Molecular Devices(Shroeder et al., J. Biomol. Screening 1: 75-80, 1996; U.S. Pat. No.5,112,134; U.S. Pat. No. 4,968,148). U373 MG cells, which endogenouslyexpress the neurokinin-1 receptor for Substance P, were obtained fromthe American Type Culture Collection and grown to confluence in 96-wellplates in modified Eagle's minimum essential medium (MEM) with 10% fetalbovine serum, 1 mM sodium pyruvate, 2 mM L-glutamine, and 1 mMnon-essential amino acids in a humidified incubator at 37° C. and5%CO₂/95% filtered air. The cells were stained with Calcium Indicatordye from Molecular Devices for thirty minutes at room temperature;compounds were added to the cells, and the cells were further incubatedfor twenty minutes. This dye is similar to Fluo-3, Fluo-4, and CalciumGreen dyes used by other researchers (Lin et al., Biotechniques 26:318-326, 1999) in that it increases in fluorescence in the presence ofcalcium; the Molecular Devices version is preferable because the cellsneed not be washed following staining with the dye. Dye was made freshon the day of the assay and included 2.5 mM probenecid, an anionexchange inhibitor which helps to keep the dye retained by the cells.Substance P was added in Hank's salt solution with 1% BSA to give afinal concentration of 1 mM and the resultant change in fluorescenceintensity was monitored for thirty seconds with an excitation wavelengthof 480 nm and an emission of 515 nm. Some wells were maintained ascontrols which were not incubated with any compound, and the peakfluorescence readings resulting from the wells which received compoundswere compared to these control wells in order to determine the degree ofinhibition.

Preferably, the compounds of this invention have an inhibition value ofbetter than or equal to 90% at 50 μM concentration in this assay. Tothis end, preferred compounds of this invention are compounds 2, 5, 8,10, 26-30, 32, 33, 37, 39, 42, 45, 50, 53, 56, 58, 60-62, 64-66, 68, 71,72, 76, 78, 79, 81, 82, 84, 86, 89, 90, 92, 94, 97, 98, 100, 102, 104,108-112, 115, 121, 122, 128, 129, 131-135 and 153. As such, thecompounds of this invention effectively inhibit binding of substance Ppeptide to its receptor neurokinin-1 and are effective in the treatmentof inflammatory diseases and central nervous system disorders.

It will be appreciated that, although specific embodiments of theinvention have been described herein for the purposes of illustration,various modifications may be made without departing from the spirit andscope of the invention. Accordingly, the invention is not limited exceptby the appended claims.

1. A fused bicyclo compound having the structure:

or pharmaceutically acceptable salt or stereoisomer thereof, wherein Yis —N(R₃)—; A is —(CR₄R_(4a))_(m)—; B is —(CR₅R_(5a))_(n)—; m is 2; n is1; R₄ and R_(5a) are, at each occurrence, the same or different andindependently an amino acid side chain moiety or an amino acid sidechain derivative; R_(4a) and R_(5a) are, at each occurrence, the same ordifferent and independently hydrogen, hydroxy, —COOH, —CONH₂, —R₆, —OR₆,—COOR₆, —COR₆ or —CONHR₆; R₆ is a lower alkyl optionally substitutedwith halogen or hydroxy; R₂ is -Z-(amino acid side chain moiety) or-Z-(amino acid side chain derivative), where Z is a direct bond or—C(═)O—, —C(═O)O—, —C(═O)NH—, —C(═NH)—, —SO₂— or —P(O)_(2,3)—; and R₁and R₃ are the same or different and independently an amino acid sidechain moiety, an amino acid side chain derivative, a peptide, a peptidederivative, a protein, -Z-(amino acid side chain moiety) or -Z-(aminoacid side chain derivative), wherein Z is a direct bond or —C(═O)—,—C(═O)O—, —C(═O)NH—, —C(═NH)—, —SO₂— or —P(O)_(2,3)—; and wherein anytwo adjacent CH groups or adjacent NH and CH groups of the fused bicyclocompound optionally form a double bond.
 2. The compound of claim 1wherein all occurrences of R₄, R_(4a), R₅ are hydrogen, and saidcompound has the structure:


3. The compound of claim 2 wherein R₁ is amino acid side chain moiety oramino acid side chain derivative, R₂ and R₃ are the same or differentand independently, -Z-(amino acid side chain moiety) or -Z-(amino acidside chain derivative), wherein Z is a direct bond or —C(═)O—, —C(═O)O—,—C(═O)NH—, —C(═NH)—, —SO₂— or —P(O)_(2,3)—.
 4. The compound of claim 3wherein Z is —C(═)O—, —C(═O)— or —C(═(O)NH—.
 5. The compound of claim 3wherein the amino acid side chain derivative is aryl, arylalkyl,heterocycle, heterocyclealkyl, heteroaryl or heteroarylalkyl optionallyand independently substituted with one or more halogen, —CF₃, —COOH,—NH₂, —OH or —NO₂.
 6. The compound of claim 3 wherein amino acid sidechain derivative is alkyl or substituted alkyl.
 7. The compound of claim6 wherein substituted alkyl is —(CH₂)_(p)—NH₂ or —(CH₂)_(p)—N(R′)₂,where p is 2-6 and R′ is independently hydrogen, alkyl or heterocycle.8. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 9. A library of compoundscomprising a plurality of library members, wherein at least one librarymember is a compound of claim
 1. 10. A method for identifying abiologically active compound, comprising screening the library ofcompounds of claim 9 for biological activity.